WO2003020303A1 - Utilisation de leptine chez les enfants de faible poids a la naissance pour la prevention de l'obesite - Google Patents

Utilisation de leptine chez les enfants de faible poids a la naissance pour la prevention de l'obesite Download PDF

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Publication number
WO2003020303A1
WO2003020303A1 PCT/GB2002/003955 GB0203955W WO03020303A1 WO 2003020303 A1 WO2003020303 A1 WO 2003020303A1 GB 0203955 W GB0203955 W GB 0203955W WO 03020303 A1 WO03020303 A1 WO 03020303A1
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Prior art keywords
leptin
infant
milk
birth weight
medicament
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PCT/GB2002/003955
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English (en)
Inventor
Michael Anthony Cawthorne
Claire Joanne Stocker
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The University Of Buckingham
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Publication date
Priority claimed from GB0120884A external-priority patent/GB0120884D0/en
Application filed by The University Of Buckingham filed Critical The University Of Buckingham
Priority to EP02755262A priority Critical patent/EP1420812A1/fr
Priority to CA002459015A priority patent/CA2459015A1/fr
Priority to US10/488,129 priority patent/US20050065078A1/en
Priority to AU2002321557A priority patent/AU2002321557B2/en
Publication of WO2003020303A1 publication Critical patent/WO2003020303A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention relates to the prevention of the development in later life of conditions, such as type 2 diabetes, obesity, cardiovascular disease, gestational diabetes, impaired glucose tolerance, insulin resistance, hypertension and syndrome X, associated with low birth weight.
  • the failure to control obesity may be due to the fact that the condition is strongly associated with genetically inherited factors that contribute to increased appetite, preference for highly caloric foods, reduced physical activity, and increased lipogenic metabolism. Thus, many people inheriting certain genetic traits are prone to becoming obese regardless of their efforts to combat the condition.
  • leptin is a feedback signal which informs the brain of the quantity of energy which is stored in the fat tissue. According to this assumption, it is then the function of the brain to decrease feed intake by inhibiting appetite, on the one hand, and to stimulate basal metabolism on the other. In human obesity, this regulatory circuit appears to be interrupted.
  • Leptin is primarily secreted from adipose tissue but is also secreted by the stomach (Bado et al, (1998), Nature 394: 790-793) and placenta (Hoggard et al, (1997), Proc.Nat. Acad. Sci. 94: 11075-11078) .
  • it acts on a number of tissues including islet cells (Emilsson et al, (1997), Diabetes 46: 313-316), skeletal muscle (Lui et al, (1997), FEBS
  • Leptin also affects fertility (Chehab et al, (1996), Nature Genetics 12: 318-320).
  • the sterility of male and female homozygous ob/ob mice was recognised since the original report of the ob mutation (Ingalls et al, (1950) J. Hered. 41: 317-318).
  • ob/ob females are always sterile whereas ob/ob males can occasionally become fertile if maintained on a restricted diet (Lane et al, (1954), J. Heredity 45: 56-58).
  • the ovaries of ob/ob females are capable of producing viable eggs when transplanted into lean female recipients (Hummel et al, (1957), Anat. Rec.
  • Leptin has been shown to restore or enhance reproductive function in reproductively impaired male or female animals and accelerated the onset of puberty (Chelab, US patent 5,773,416).
  • leptin increases early during gestation, derived primarily from the placenta (Masuzaki et al, (1997), Nature Medicine 3: 1029-1033). Although leptin and its receptor messenger RNA are expressed by the placenta (Hoggard et al, (1997), Proc. Natl . Acad. Sci. 94: 11075-11078) the role of increased leptin during pregnancy in maternal-fetal metabolism and intrauterine growth remains unclear. Schulz et al, (2000), BJOG 107: 1486-1491, concluded from studies in humans that circulating maternal leptin levels may provide a growth promoting signal for fetal development in late pregnancy and Yamashita et al, (2001) ,
  • Endocrinology 142: 2888-2897 using an animal model of spontaneous gestation diabetes, showed that leptin administration during late gestation can prevent gestational diabetes but did not prevent fetal overgrowth.
  • a factor that might mediate the in utero programming is increased fetal exposure to glucocorticoids (Bjorntorp et al (2000), Int. J. Obesity 24, Suppl. 2, S80-S85; Seckl et al (2000, Kidney Int. 57, 1412-1417) .
  • High fetal glucocorticoid levels in the small baby syndrome may result from decreased expression of type 2 ll ⁇ -hydroxysteroid dehydrogenase in the placenta.
  • This enzyme normally protects fetal tissues from the high maternal levels of cortisol (corticosterone in rats) by catalysing the conversion of cortisol (corticosterone) to inert cortisone (11 dehydrocorticosterone) (Seckl et al (2000) Kidney Int. 57, 1412-1417).
  • Type 1 ll ⁇ -hydroxysteroid dehydrogenase catalyses the reverse reaction and results in the production of cortisol from cortisone.
  • the present invention provides the use of leptin, or a fragment or mimetic thereof, for the preparation of a medicament for administration to
  • Low birth weight is used herein to refer to low birth weight for age, as a result of in utero growth retardation, for example caused by inadequate nutrition. It is not intended to refer to low birth weight as a result of premature delivery. What is considered to be a normal birth weight for age will be determined by different factors in different species. For example, birth weight may vary according to e.g. sex and ethnicity of the offspring in humans. In general, birth weight may be considered to be low if it is within the lower two quintiles of the range observed in an appropriately matched population. Where methods are referred to herein, the present invention further provides leptin, or a fragment or mimetic thereof, for use in those methods. Thus, inter alia, the present invention provides leptin for administration to (i) an infant of low birth weight for age;
  • the present invention further provides a method for preventing the development in later life of a metabolic disorder or other condition associated with low birth weight in an infant having low birth weight for age, the method comprising providing the infant with a prophylactically effective amount of leptin, or a fragment or mimetic thereof.
  • the present invention further provides a method for preventing the development in later life of an infant of a metabolic disorder or other condition associated with low birth weight, the method comprising providing a pregnant female, predisposed to giving birth to an infant having low birth weight for age, with a prophylactically effective amount of leptin, or fragment or mimetic thereof.
  • Conditions thought to be associated with low birth weight include type 2 diabetes, obesity, cardiovascular disease, gestational diabetes, impaired glucose tolerance, insulin resistance, hypertension and syndrome X, also known as insulin resistance syndrome .
  • leptin or a fragment or mimetic thereof, is provided to an infant, either in utero, or after birth, to prevent or ameliorate the development during later life of the metabolic disorder or other condition associated with low birth weight.
  • Leptin, fragments, and mimetic thereof may be provided to an infant post partum, either directly, for example in admixture with milk, or indirectly, by administration to a nursing mother (i.e. a lactating female) , in order that the active agent is delivered to the infant via the mother's milk.
  • a nursing mother i.e. a lactating female
  • the female need not be the mother of the infant in question, as long as she is lactating and is capable of feeding the infant.
  • leptin, or a fragment or mimetic thereof can favourably influence the metabolic programming imposed upon her offspring.
  • leptin, or fragments or mimetics thereof may be provided to a pregnant female to prevent or ameliorate the development in her offspring of a metabolic disorder or other condition associated with low birth weight.
  • the leptin, or fragment or mimetic thereof may be particularly effective when provided to the pregnant female during the third trimester of pregnancy.
  • a female predisposed to give birth to an infant of low weight for age is any female suspected to have a higher than normal chance of giving birth to such an infant. This assessment may be made based on her previous reproductive history, on physical assessment of the foetus during gestation, e.g. by means of a scan, or because of her nutritional status, lifestyle, or medical status. A number of factors affect the chance of females having small for date offspring. In humans, women who smoke or have asthma have a significantly greater chance than normal of having a small for date baby. Malnutrition, especially protein malnutrition, during pregnancy is also a significant cause of small for date offspring. In all species, females who have already had one or more small for date offspring will be at greater risk than normal of having further such offspring. Thus candidate females will be readily identifiable by clinicians, veterinarians, etc. Any suitable scanning technology may be applied during gestation to provide further data about whether or not offspring are likely to be small for date.
  • leptin or a fragment or mimetic thereof, to a pregnant female or nursing mother or directly to the infant during the pre-weaning period will favourably influence the metabolic programming of female offspring, so that when those female offspring themselves reproduce, gestational diabetes is prevented and normal offspring are produced.
  • compositions e.g. medicaments and foodstuffs
  • the methods and compositions are suitable for application or administration to any mammal, but especially to humans and domestic animals, such as cats and dogs.
  • leptin, or a fragment or mimetic thereof may be provided to infant humans or animals post partum to prevent or ameliorate the development during later life of metabolic disorders or other condition associated with low birth weight.
  • suitable active agents may be provided to a pregnant or lactating female.
  • compositions of the present invention are considered most efficacious when applied to infants in utero or before weaning. Thus in humans, infants will benefit most when treated in utero or in the first six months post partum, preferably in the first three months post partum. Suitable treatment times for other species may be calculated accordingly.
  • the present invention also provides a kit comprising leptin and instructions for administration to a pregnant female, a nursing mother, or an infant.
  • the invention further provides a method of preparing a medicament or foodstuff, comprising the step of admixing milk with leptin or a fragment or mimetic thereof.
  • the present invention contemplates a method of adding leptin to milk derived from the same species, e.g. adding human leptin to human breast milk, e.g. full-term breast milk.
  • the leptin is derived from a first mammalian species, and the milk from a different source, such as a second mammalian species.
  • the leptin may be, for example, human leptin, or be from a domestic animal, such as canine or feline leptin.
  • a method of preparing a medicament or foodstuff comprising the step of admixing human leptin and animal milk, preferably milk from an agricultural dairy animal, e.g. cow, sheep or goat milk.
  • the present invention further provides a medicament or foodstuff, comprising leptin, or a fragment or mimetic thereof, from a first mammalian species and milk from a different source, for example, from a second mammalian species, such as cows, goats, or sheep.
  • a second mammalian species such as cows, goats, or sheep.
  • the leptin is human, or from a domestic animal, e.g. feline or canine leptin.
  • a medicament or foodstuff comprising human leptin and animal milk, e.g. cow, sheep or goat milk.
  • Agents capable of enhancing endogenous levels of leptin in the individual to which they are administered may also be used in any of the methods or compositions of the present invention.
  • Such agents may increase the expression of endogenous leptin; for example, an diet which is deficient in essential fatty acids and high in saturated fatty acids and fatty acids having a low degree of polyunsaturation has been proposed to increase leptin levels (Korotkova, M, et al . , (2002) Pediatric Research 52(1): 78-84).
  • the present invention further provides the use of an agent capable of enhancing endogenous levels of leptin for the manufacture of a medicament for administration to
  • leptin may exert the effects described through an increase in the activity of placental type 2 ll ⁇ -hydroxysteroid dehydrogenase (HSD-2) .
  • leptin may increase the activity of HSD-2 which converts the stress hormone cortisol (or its equivalent, corticosterone, found e.g. in rodents) to the inactive molecule cortisone (or dehydrocorticosterone) , and so may protect the developing foetus from the effects of placental cortisol/corticosterone .
  • cortisol is intended to embrace all equivalents of cortisol in other mammals, e.g. corticosterone.
  • leptin may be administered in conjunction with an agent capable of reducing cortisol bioactivity in the individual to which it is administered, either systemically, e.g. in the circulation, or in a specific tissue type.
  • an agent capable of reducing cortisol bioactivity in the individual to which it is administered, either systemically, e.g. in the circulation, or in a specific tissue type.
  • Such an agent may be a direct antagonist of cortisol which prevents the cortisol molecule from exerting its normal biological effects, e.g. by preventing interaction of cortisol with its receptor, or blocking the cortisol effector pathway.
  • Such an agent may, for example, be a neutralising antibody capable of binding cortisol.
  • the agent may be capable of modulating cortisol concentration, e.g. modulating synthesis or degradation of cortisol.
  • the agent may increase the rate of inactivation of cortisol, e.g. by stimulating HSD-2 activity or expression.
  • HSD-2 may be administered directly to increase the rate of inactivation of cortisol.
  • the agent may decrease the rate of synthesis of cortisol by inhibiting HSD-1 activity or expression.
  • Suitable inhibitors may include BT 2733 and BVT 14225 (Barf et al . , 2002, above). Any suitable method for modulating expression of HSD-1 may be used.
  • the agent is capable of inhibiting HSD-1 activity or expression.
  • HSD-1 and HSD-2 have opposing activities, it is believed that an inhibitor of HSD-1 acting in combination with an activator of HSD-2 (such as leptin) will have a synergistic effect; that is to say the effect of using two such agents together will be greater than the sum of the effects obtained using each agent individually.
  • the increased sensitivity of response may be similar to that observed with metabolic substrate cycles, in which a relatively small change in concentration of a regulator molecule capable of allosterically regulating both enzymes of a substrate cycle can cause a much larger change in the net flux through the pathway.
  • this aspect of the invention may be particularly suitable for administration to pregnant females, for in utero treatment.
  • Figure 1 shows growth of offspring of female rats fed on an 8% protein diet, and given a saline infusion from day 14 of pregnancy.
  • Figure 2 shows growth of offspring of female rats fed on an 8% protein diet, and given an infusion of leptin from day 14 of pregnancy.
  • Figure 3 shows plasma leptin concentration in female rats fed on normal 20% protein diet (NPS) and on an isocaloric low 8% protein diet with either an infusion of saline (LPS) or leptin (LPL) from day 14 of pregnancy and throughout lactation.
  • NPS normal 20% protein diet
  • LPS isocaloric low 8% protein diet
  • LPL leptin
  • Figure 4 shows the placental weights in female rats fed on a normal 20% protein diet (NPS) or on an isocaloric low 8% protein diet with either an infusion of saline (LPS) or leptin (LPL) from day 14 of pregnancy.
  • Figure 5 shows the birthweight of offspring from mothers fed on a normal 20% protein diet (NPS) or fed on an isocaloric low 8% protein diet with either an infusion of saline (LPS) or leptin (LPL) from day 14 of pregnancy.
  • Figure 6 shows the body weight of pups during lactation from mothers fed on a normal 20% protein diet (NPS) and on an isocaloric 8% protein diet with either an infusion of saline (LPS) or leptin (LPL) from day 14 of pregnancy and throughout lactation.
  • NPS normal 20% protein diet
  • LPS leptin
  • Figure 7 shows growth of the male offspring fed on a high fat diet, from mothers that had been fed on a normal 20% protein diet.
  • Figure 8 shows growth of the male offspring fed on a high fat diet, from mothers that had been fed on an isocaloric low (8%) protein diet, and given a saline infusion from day 14 of pregnancy and throughout lactation.
  • Figure 9 shows the growth of the male offspring fed on a high fat diet, from mothers that had been fed on an isocaloric low (8%) protein diet, and given an infusion of leptin from day 14 of pregnancy and throughout lactation.
  • Figure 10 shows the fasting insulin concentration of male offspring fed on a high fat diet, from mothers that had been fed on a normal 20% protein diet.
  • Figure 11 shows fasting insulin concentration of male offspring fed on a high fat diet, from mothers that had been fed on an isocaloric low (8%) protein diet and given a saline infusion from day 14 of pregnancy and throughout lactation.
  • Figure 12 shows the fasting insulin concentration of male offspring fed on a high fat diet, from mothers that had been fed on an isocaloric low (8%) protein diet and given an infusion of leptin from day 14 or pregnancy and throughout lactation.
  • Figure 13 shows the integrated blood glucose concentration during a glucose tolerance test in 6 and 12 month old rats.
  • Figure 14 shows the integrated plasma insulin concentration during a glucose tolerance test in 6 and 12 month old rats.
  • Figure 15 shows the plasma corticosterone levels in dams during pregnancy and lactation.
  • Figure 16 shows the activity of ll ⁇ -hydroxysteroid dehydrogenase-1 (HSD-1) and ll ⁇ -hydroxysteroid dehydrogenase-2 (HSD-2) in the placenta at day 20.5 of pregnancy.
  • Conditions which may be prevented or ameliorated in later life by the methods and compositions of the present invention include any metabolic disorder associated with low birth weight for date, including type 2 diabetes, obesity, cardiovascular disease, gestational diabetes, impaired glucose tolerance, insulin resistance, hypertension and syndrome X.
  • Syndrome X also known as insulin resistance syndrome, is a description given to a variety of symptoms of metabolic dysregulation which precede development of a major metabolic disorder such as type II diabetes. Syndrome X is characterised by one or more of glucose intolerance, increased plasma triglycerides, increased low and very low density lipoproteins, decreased high density hdl-cholesterol, post-prandial lipaemia, increased serum uric acid, slight increase in blood pressure, and increased plasminogen activator inhibitor 1.
  • Active agents suitable for use in the present invention include full-length leptin polypeptides including modified molecules containing adducts such as dextran, fatty acids or pegylated moieties, or biologically active fragments or mimetics thereof.
  • Leptin polypeptides may be isolated from physiological sources, or recombinantly produced. Recombinant polypeptides may be produced in any appropriate expression system, such as mammalian, insect, bacterial or yeast expression systems, and may be produced with or without their naturally occurring secretion signal peptides.
  • the present invention is applicable for the treatment of mammals, and in preferred embodiments for the treatment of humans and domestic animals, such as dogs and cats.
  • leptin, or fragments thereof When natural or recombinant leptin, or fragments thereof are used, they will preferably be derived from the species which it is to be used to treat. Thus humans will preferably be treated with human leptin.
  • leptins may be used to treat species other than those from which they are derived.
  • the leptin is derived from human, cat, dog, mouse, pig, anthropoid ape, bovine or ovine sources.
  • clearly other forms of leptin can be used for treatment of other species.
  • Biologically active leptin fragments and mimetics are also suitable for use in the present invention. Fragments include peptides derived from full-length leptin polypeptides, and truncated recombinant forms of leptin. Suitable leptin fragments include those disclosed in US patent number 6187751, W097/46585 and WO00/11173. Mimetics are considered to be active agents sharing one or more biological activities with leptin. They may be naturally occurring polypeptides sharing biological activities with leptin, such as for example, human obesity protein homologue-1, as disclosed in
  • WO01/25428 and ciliary neurotrophic factor activators including Axokine as disclosed in W098/22128.
  • a mimetic may be a recombinant leptin polypeptide having amino acid substitutions, deletions or insertions relative to a native leptin sequence, which substantially retain or have enhanced leptin biological activity.
  • a mimetic may be a synthetic small molecule, peptide or polypeptide drug capable of exerting one or more biological effects of leptin.
  • the designing of mimetics to a known pharmaceutically active compound is a known approach to the development of pharmaceuticals based on a "lead" compound. This might be desirable where the active compound is difficult or expensive to synthesise or where it is unsuitable for a particular method of administration, eg peptides may be unsuitable active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal.
  • Mimetic design, synthesis and testing is generally used to avoid randomly screening large number of molecules for a target property.
  • a mimetic from a compound having a given target property There are several steps commonly taken in the design of a mimetic from a compound having a given target property. Firstly, the particular parts of the compound that are critical and/or important in determining the target property are determined. In the case of a peptide, this can be done by systematically varying the amino acid residues in the peptide, eg by substituting each residue in turn. These parts or residues constituting the active region of the compound are known as its "pharmacophore" . Once the pharmacophore has been found, its structure is modelled to according its physical properties, e.g. stereochemistry, bonding, size and/or charge, using data from a range of sources, e.g. spectroscopic techniques, X-ray diffraction data and NMR. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modelling process.
  • the three-dimensional structure of the ligand and its binding partner are modelled. This can be especially useful where the ligand and/or binding partner change conformation on binding, allowing the model to take account of this in the design of the mimetic.
  • a template molecule is then selected onto which chemical groups which mimic the pharmacophore can be grafted.
  • the template molecule and the chemical groups grafted on to it can conveniently be selected so that the mimetic is easy to synthesise, is likely to be pharmacologically acceptable, and does not degrade in vivo, while retaining the biological activity of the lead compound.
  • the mimetic or mimetics found by this approach can then be screened to see whether they have the target property, or to what extent they exhibit it. Further optimisation or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.
  • Leptins, leptin fragments, or mimetics fused to non-leptin polypeptides, or conjugated to small-molecule carriers are also suitable for use in the present the invention.
  • the non-leptin polypeptide or carrier may influence biological availability or pharmacokinetics, such as half life in the blood stream.
  • Suitable fusion partners or carriers will be well known to the person skilled in the art, and include for example immunoglobulin Fc regions . Without wishing to be bound by any particular theory, it is believed that administration of leptin to offspring following parturition is effective in overcoming the metabolic programming imposed on the offspring in utero.
  • the leptin, or fragment or mimetic thereof is provided to an infant to prevent or ameliorate the development during later life of a metabolic disorder or other condition associated with low birth weight.
  • the leptin, fragment or mimetic thereof may be provided to an infant in milk.
  • the leptin, fragment or mimetic thereof may be provided to an infant indirectly, by administration of the agent to a nursing mother, in order that the active agent is delivered to the infant in the mother's milk.
  • the administration of leptin to a pregnant female can favourably influence the metabolic programming imposed upon her offspring.
  • the leptin, or fragment or mimetic thereof is provided to a pregnant female to prevent or ameliorate the development in her offspring of the metabolic disorder or other condition associated with low birth weight.
  • the leptin, or fragment or mimetic thereof may be particularly effective when provided to the pregnant female during the third trimester of pregnancy.
  • Leptin may be administered orally to an infant, either formulated as a pharmaceutical, or in admixture with milk. This is because proteins are absorbed intact from the infant alimentary canal into the bloodstream, without proteolysis or degradation. Protein given orally to an adult will typically be degraded in the alimentary canal. Therefore when an active agent to be administered to a pregnant or nursing female is a protein, peptide or polypeptide, it will typically be formulated as a pharmaceutical for administration by other than oral means.
  • Pharmaceutical compositions may comprise, in addition to one or more active agents, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • Suitable pharmaceutically acceptable carriers are as dictated by conventional practice such as those disclosed in GB 2292382 or in International Patent Application Publication number WO 94/01420. They also include pharmaceutically acceptable carriers, which are compatible with incorporation into milk powders and liquid milk. This is particularly appropriate for administration direct to an infant. Leptin, and fragments and mimetics thereof may be provided in admixture with animal milk or human breast milk, or in any suitable formulation of powdered or dried milk, either prior to or after reconstitution.
  • the invention further provides a method of preparing a medicament or foodstuff, comprising the step of admixing milk with leptin or a fragment or mimetic thereof.
  • the present invention contemplates a method of adding leptin to milk derived from the same species, e.g. adding human leptin to human breast milk, e.g. full-term breast milk.
  • the leptin is derived from a first mammalian species, and the milk from a different source, for example from a second mammalian species.
  • the leptin may be, for example, human leptin, or be from a domestic animal, such as canine or feline leptin.
  • a method of preparing a medicament or foodstuff comprising the step of admixing human leptin and animal milk, e.g. cow, sheep or goat milk.
  • animal milk e.g. cow, sheep or goat milk.
  • ⁇ milk' is used herein to refer to milk from any mammalian species, in treated or untreated form, as well as to milk substitutes intended to provide nutrition for infants.
  • milk' encompasses human or animal milk in full, semi-skimmed or skimmed form, in liquid, powder or concentrate form, pasteurised or unpasteurised.
  • infant formula typically comprises milk derivatives with additional nutritional supplements, which are readily commercially available, as well as artificial milk substitutes such as soya milk, which typically comprise non-animal protein, optionally supplemented by sugars, other carbohydrates, fats, and other nutritional additives.
  • the mode of admixture will depend upon the form of the milk to which the leptin is to be added, and will be chosen so as to retain leptin activity in the final mixture.
  • milk is often sterilised by heat treatment, e.g. by pasteurisation.
  • Leptin activity may be affected by heat treatment, so leptin may be added to milk after sterilisation, in order that leptin activity is not adversely affected by the sterilisation process.
  • the active agent may be administered subcutaneously, intradermally, intravenously, intramuscularly, intraperitoneally, via pulmonary delivery, via intranasal delivery, transdermally, orally, via controlled release, via pump or by any conventional route of administration for polypeptide drugs.
  • the agent will be administered continuously during the period of administration, i.e. being delivered at least once per day or via controlled release techniques via a transdermal patch or a sustained release injectable formulation providing, for example, a 28d supply.
  • compositions may comprise a solution of leptin, or a fragment or mimetic thereof, dissolved or suspended in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers may be used, e.g., water, buffered water, 0.8% saline, 0.3% glycine, hyaluronic acid and the like.
  • These compositions may be sterilised by conventional, well known sterilisation techniques, or may be sterile filtered.
  • the resulting aqueous solutions may be packaged for use as is, or lyophilised, the lyophilised preparation being combined with a sterile solution prior to administration.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • auxiliary substances such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • the concentration of the leptin, fragment, or mimetic thereof in the pharmaceutical formulations can vary widely, i.e., from less than about 0.1%, usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.
  • the leptin, or fragment or mimetic thereof When administered in milk, the leptin, or fragment or mimetic thereof will typically have an activity corresponding to a solution in milk of up to 30ng/ml of full-length leptin from the same species as the subject.
  • the leptin activity will correspond to that of a solution in milk of 2 to 20ng/ml of full- length human leptin, preferably 10 to 20ng/ml.
  • non-toxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • a pharmaceutically acceptable non- toxic composition is formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally 10%-95% of active ingredient, that is, one or more leptin compounds of the invention, and more preferably at a concentration of 25%-75%.
  • the active agent is preferably supplied in finely divided form along with a surfactant and propellant.
  • Typical percentages of leptin are 0.01%-20% by weight, preferably 1%-10%.
  • the surfactant must, of course, be non-toxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhdric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides may be employed.
  • the surfactant may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.
  • compositions of the invention can additionally be delivered in a controlled release system such as a depot-type system, an encapsulated form, or an implant by techniques well- known in the art.
  • the compositions of the invention can also be delivered via a pump, such as a minipump, to pregnant female host and/or to preweaned offspring.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • Administration is preferably in a "prophylactically effective amount” or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy) , this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed) , 1980.
  • full length leptin will usually be administered in a dosage from O.lng/kg body weight to lOOmg/kg body weight to either or both the pregnant female or the offspring.
  • Amounts effective for use will depend on, for example, the particular active agent, the method of formulation, the manner of administration, and the weight of the patient.
  • targeting therapies may be used to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibody or cell specific ligands. Targeting may be desirable for a variety of reasons; for example if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
  • these agents could be produced in target cells by expression from an encoding gene introduced into the cells, eg in a viral vector (a variant of the VDEPT technique - see below) .
  • the vector could be targeted to the specific cells to be treated, or it could contain regulatory elements which are switched on more or less selectively by the target cells.
  • the agent could be administered in a precursor form, for conversion to the active form by an activating agent produced in, or targeted to, the cells to be treated.
  • an activating agent produced in, or targeted to, the cells to be treated.
  • This type of approach is sometimes known as ADEPT or VDEPT; the former involving targeting the activating agent to the cells by conjugation to a cell-specific antibody, while the latter involves producing the activating agent, eg an enzyme, in a vector by expression from encoding DNA in a viral vector (see for example, EP-A-415731 and WO 90/07936) .
  • the female When the methods of the present invention are to be used to administer active agents to a pregnant female, the female will usually suffer from a nutritional or other disorder or a lifestyle disorder such as smoking that results in the production of a small for date offspring.
  • the female host may be lean, of normal adiposity or obese.
  • the active agent is administered to the pregnant host during the 3 rd trimester.
  • the active agent When the methods of the present invention are used to administer active agents to offspring post-partum, either via mother's milk or via direct administration, the active agent will typically be administered to the offspring during at least a portion of the first 3 months of life. Preferably, the active agent is administered throughout the first three months of life.
  • the active agent when the active agent is to be administered via mother' s milk, the active agent will typically be administered to a female host during at least a portion of the first 3 months of lactation, and preferably throughout the entire period of lactation.
  • the present invention also provides a method of preventing the development of a metabolic disorder or other condition associated with low birth weight in a patient, the method comprising providing the patient with a prophylactically effective amount of leptin, or a fragment or mimetic thereof.
  • agents capable of reducing cortisol (or corticosterone) bioactivity may be administered in conjunction with the leptin, fragment or mimetic thereof.
  • agents may be administered as part of a medicament or foodstuff, or in milk.
  • the agent capable of reducing cortisol bioactivity and leptin may be administered individually or together, in the same or different foodstuffs, milk formulations or medicaments.
  • the agent capable of reducing cortisol bioactivity is administered in a pharmaceutically acceptable quantity and form.
  • Pregnant rats were fed on either a control diet containing 20% protein or an isocalorific diet containing 8% protein throughout pregnancy and lactation. On day 14 of pregnancy (at the beginning of third trimester) rats on the 8% protein diet were assigned to a control group or a leptin-treated group. Each rat received a continuous infusion of saline or leptin for 28 days via a subcutaneous minipump.
  • the group receiving leptin were given lmg/kg/day as a continuous infusion from an Alzet mini-pump model 2ML4, at 2.5 microlitres per hour for 28 days Pups were weaned at day 21 onto the control 20% protein diet and then at 6 weeks of age transferred to either a control or high fat diet until 8 months of age.
  • Leptin infusion significantly elevated plasma levels in the pregnant rats fed on a low protein diet. Leptin infusion reduced voluntary food intake in the pregnant rats fed on a low protein diet during pregnancy and reduced the post-birth maternal body weight .
  • Leptin treatment did not affect the live litter size, the birth weight of pups or the placental weight.
  • the birth weight of pups from mothers receiving the 8% protein diet was significantly lower than the birth weight of pups on a 20% protein diet.
  • the weight at 21 days of age of pups from mothers on the 8% protein diet was less than those from mothers on the 20% protein diet but leptin treatment had no additional influence.
  • Pregnant Wistar rats were fed on either a normal (20% protein) diet or an isocaloric diet containing 8% protein throughout pregnancy and lactation. From day 14 of pregnancy they received saline or leptin (2mg/kg/day) via a subcutaneous minipump (Alzet Corp.) for 28 days. All pups were weaned at 21 days old onto a 20% protein diet and at 6 weeks of age some of the pups were transferred to a high fat diet (60% of calories provided by fat) .
  • a glucose tolerance test was performed at 6 months of age. In addition measurements were made of glucose and insulin throughout the study and during the glucose tolerance test to assess insulin sensitivity.
  • Plasma leptin concentrations in the mothers given leptin were increased 5-fold (Figure 3) relative to the concentration in mothers not given leptin, but had only a minor effect on maternal food intake and body weight.
  • the litter size was the same in all three groups. Placental weights were lower in low protein diet mothers ( Figure 4) but birth weight of offspring of low protein fed rats given leptin was the same as offspring from rats given a normal protein diet and greater than those from rats given a low protein diet and infused with saline ( Figure 5) . However, post- birth during lactation the weight of pups from leptin-treated mothers given a low protein diet was the same as that of pups from mothers on the same diet but not given leptin (Figure 6) .
  • pancreatic insulin content in pups from saline-treated mothers given a low protein diet were significantly lower (4.0 ⁇ 0.7 ⁇ g/ pancreas) than in pups from mothers on the normal protein diet (6.2 + 1.4 ⁇ g/ pancreas).
  • Leptin treatment of the low protein diet mothers resulted in a significant increase in the pancreatic insulin content in 2 day old pups (6.4 ⁇ 1.0 ⁇ g/pancreas) .
  • Glucagon and amylin content of the pancreas of 2 day old pups was not affected by prior dietary manipulation or leptin administration to the mother. Glucose tolerance was undertaken at 6 weeks of age.
  • the low protein saline offspring were more insulin sensitive than the normal protein saline offspring and this was not altered by leptin treatment At 6 weeks of age, some of the rats were placed on a high fat diet whereas the remainder continued on the normal protein diet.
  • the high fat diet mirrors in composition the typical Western diet.
  • the high fat diet induced obesity in offspring from mothers given both the normal protein ( Figure 7) and low protein diet ( Figure 8), but the additional treatment of the low protein diet mothers with leptin prevented the high fat diet induced obesity ( Figure 9) .
  • the integrated areas of the plasma insulin concentration during the period 0-2h post the glucose load are given in Figure 14.
  • the high fat diet fed offspring of the leptin-treated dams given the low protein diet had a significantly reduced insulin output relative to high-fat diet fed offspring of dams given saline plus the low- protein diet or the normal protein diet. This indicates increased insulin sensitivity in the offspring of leptin-treated dams.
  • the corticosterone levels of the dams given either the normal protein diet or the low protein diet did not differ irrespective of the administration of leptin (Figure 15) .
  • Intraperitoneal glucose tolerance tests were conducted in rats at 6 weeks, 6 months and 12 months of age. Prior to the procedure rats, were fasted overnight and then dosed with glucose (lg/kg, i.p). Blood samples were taken from the tail for glucose and insulin measurements at 0, 30, 60, 90, 120 and 180 minutes after glucose injection. Glucose tolerance was assessed in terms of areas under the glucose-time curves.
  • Glucose tolerance, plasma levels and pancreatic hormone measurements were analysed using Dunnett's Multiple comparison oneway analysis of variance (ANOVA) . Results are presented as means + s .e .m.

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Abstract

L'invention concerne l'administration thérapeutique et prophylactique de leptine à : (i) un enfant de faible poids de naissance; (ii) une mère allaitante d'un enfant ayant un faible poids de naissance; ou (iii) une femme enceinte prédisposée à accoucher d'un enfant de faible poids à la naissance. Cette administration permet la prévention ou le traitement, dans la vie de l'enfant, de troubles métaboliques ou d'autres états pathologiques associés au faible poids à la naissance, tels que le diabète de type 2, l'obésité, les maladies cardio-vasculaires, le diabète gestationnel, la tolérance diminuée à la glucose, la résistance à l'insuline, l'hypertension ou le syndrome X. Il est vraisemblable que les propriétés salutaires de la peptine puissent être dues au moins en partie à un effet sur le métabolisme des glucocorticoïdes, notamment à une augmentation de l'activité de type 2 11β-hydroxystéroïde déshydrogénase.
PCT/GB2002/003955 2001-08-29 2002-08-28 Utilisation de leptine chez les enfants de faible poids a la naissance pour la prevention de l'obesite WO2003020303A1 (fr)

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EP02755262A EP1420812A1 (fr) 2001-08-29 2002-08-28 Utilisation de leptine chez les enfants de faible poids a la naissance pour la prevention de l'obesite
CA002459015A CA2459015A1 (fr) 2001-08-29 2002-08-28 Utilisation de leptine chez les enfants de faible poids a la naissance pour la prevention de l'obesite
US10/488,129 US20050065078A1 (en) 2001-08-29 2002-08-28 Use of leptin for infant with low birth weight for prevention of obesity
AU2002321557A AU2002321557B2 (en) 2001-08-29 2002-08-28 Use of leptin for infant with low birth weight for prevention of obesity

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GB0120884A GB0120884D0 (en) 2001-08-29 2001-08-29 Materials and methods for prevention of obesity
GB0120884.2 2001-08-29
GB0211936.0 2002-05-23
GB0211936A GB0211936D0 (en) 2001-08-29 2002-05-23 Materials and methods for prevention of obesity

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ES2190888A1 (es) * 2001-12-03 2003-08-16 Univerdad De Les Silles Balear Nuevas aplicaciones de la leptina como suplemento nutricional
WO2006089987A1 (fr) * 2005-02-23 2006-08-31 Universitat De Les Illes Balears Utilisation de la leptine dans la prevention d'une surcharge ponderale et composition contenant de la leptine
EP1862181A2 (fr) * 2003-04-11 2007-12-05 Novo Nordisk A/S Polythérapie utilisant un inhibiteur de la 11B-hydroxystéroïde déshydrogénase de type 1 et agent anti-hypertensif pour le traitement du syndrome métabolique et maladies et troubles associés
WO2008155403A2 (fr) * 2007-06-20 2008-12-24 Universitat De Les Illes Balears Utilisation de la leptine dans la prévention d'habitudes alimentaires nuisibles pour la santé et de maladies cardiovasculaires
EP2005967A1 (fr) * 2007-06-20 2008-12-24 Universitat de les Illes Balears Utilisation de leptine pour le traitement d'altérations d'habitudes alimentaires
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US8642543B2 (en) 2005-09-07 2014-02-04 Neurotez, Inc. Methods for treating progressive cognitive disorders related to neurofibrillary tangles
US8716220B2 (en) 2005-09-07 2014-05-06 Nikolaos Tezapsidis Leptin compositions and methods for treating progressive cognitive function disorders resulting from accumulation of neurofibrillary tangles and amyloid beta

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US8227408B2 (en) * 2005-09-07 2012-07-24 Neurotez, Inc. Leptin as an anti-amyloidogenic biologic and methods for delaying the onset and reducing Alzheimer's disease-like pathology
US9662059B2 (en) * 2007-04-26 2017-05-30 The Regents Of The University Of California Imaging agents for monitoring changes of dopamine receptors and methods of using thereof

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WO2000047741A1 (fr) * 1999-02-12 2000-08-17 Amgen Inc. Compositions glycosylees de leptine et procedes correspondants
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2190888A1 (es) * 2001-12-03 2003-08-16 Univerdad De Les Silles Balear Nuevas aplicaciones de la leptina como suplemento nutricional
EP1862181A2 (fr) * 2003-04-11 2007-12-05 Novo Nordisk A/S Polythérapie utilisant un inhibiteur de la 11B-hydroxystéroïde déshydrogénase de type 1 et agent anti-hypertensif pour le traitement du syndrome métabolique et maladies et troubles associés
EP1862181A3 (fr) * 2003-04-11 2010-09-15 High Point Pharmaceuticals, LLC Polythérapie utilisant un inhibiteur de la 11B-hydroxystéroïde déshydrogénase de type 1 et agent anti-hypertensif pour le traitement du syndrome métabolique et maladies et troubles associés
WO2006089987A1 (fr) * 2005-02-23 2006-08-31 Universitat De Les Illes Balears Utilisation de la leptine dans la prevention d'une surcharge ponderale et composition contenant de la leptine
ES2258923A1 (es) * 2005-02-23 2006-09-01 Universitat De Les Illes Balears Uso de la leptina para la prevencion del exceso de peso corporal y composicion que contiene leptina.
US7759339B2 (en) 2005-03-31 2010-07-20 Takeda San Diego, Inc. Hydroxysteroid dehydrogenase inhibitors
US8642543B2 (en) 2005-09-07 2014-02-04 Neurotez, Inc. Methods for treating progressive cognitive disorders related to neurofibrillary tangles
US8716220B2 (en) 2005-09-07 2014-05-06 Nikolaos Tezapsidis Leptin compositions and methods for treating progressive cognitive function disorders resulting from accumulation of neurofibrillary tangles and amyloid beta
WO2008155403A2 (fr) * 2007-06-20 2008-12-24 Universitat De Les Illes Balears Utilisation de la leptine dans la prévention d'habitudes alimentaires nuisibles pour la santé et de maladies cardiovasculaires
EP2005967A1 (fr) * 2007-06-20 2008-12-24 Universitat de les Illes Balears Utilisation de leptine pour le traitement d'altérations d'habitudes alimentaires
ES2319048A1 (es) * 2007-06-20 2009-05-01 Universitat De Les Illes Balears Uso de leptina en el tratamiento de alteraciones en los habitos alimentarios.
WO2008155403A3 (fr) * 2007-06-20 2009-07-02 Univ Illes Balears Utilisation de la leptine dans la prévention d'habitudes alimentaires nuisibles pour la santé et de maladies cardiovasculaires

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